Intensive therapy has cured 70-75% of children diagnosed with acute lymphoblastic leukemia (ALL); most have sequelae of treatment. In this Project, we will assess the long-term outcome of antileukemia therapy and augment the usual event-free survival comparisons of treatment programs by use of methods to adjust survival for its quality. The focus will be on those aspects of our treatment program that have contributed to increased prevention of leukemia relapse, but have been associated with late sequelae. Specifically, we will concentrate on evaluating doxorubicin- induced cardiotoxicity, central nervous system (CNS) treatment-induced neuropsychological toxicity, and overall health-related quality of life. In the context of a prospective randomized clinical trial, we will determine whether the cardioprotectant drug ADR-529 (ICRF-187) diminishes late doxorubicin-induced cardiotoxicity. We will also assess the value of serial cardiac monitoring during doxorubicin therapy. We will determine the relative efficacy of intensive intrathecal therapy compared to hyperfractionated cranial radiation, an innovative CNS treatment which we began to study in 1987 in order to decrease CNS toxicity in high risk patients. No child randomized to this radiation schedule between 1987- 1991 has had a CNS relapse (N=84), compared with one CNS relapse among children randomized to receive conventional radiation (N=97). Hyperfractionated cranial radiation will be evaluated for its long-term toxicity compared to conventional cranial radiation. Quality-adjusted survival analysis using Q-TWiST and QALY methods will characterize the trade-off between the benefit of improved cure rates and the cost in terms of treatment-related toxicity. We seek to determine the most effective, least toxic therapies for childhood ALL, balancing the health-related quality of life against the rate of cure to maximize the therapeutic ratio.